This invention relates to the field of antivirals and in particular to HIV reverse transcriptase inhibitors. The invention provides novel compounds, pharmaceutical compositions comprising these compounds and methods for the inhibition of HIV employing them.
Of the pharmaceuticals which have shown clinically relevant activity in the inhibition of HIV reverse transcriptase in HIV treatment, most are nucleoside analogues such as AZT, ddI, ddC and D4T. These nucleoside analogues are not as specific as is desirable and thus have to be administered at relatively high dosage levels. At these dosage levels, nucleoside analogues tend to be rather toxic, limiting their long term use.
To overcome these problems of specificity and toxicity a number of non-nucleoside inhibitors of the reverse transcriptase of HIV have been developed. For example TIBO, a reverse transcriptase from Janssen inhibits HIV at nanomolar concentrations and displays no clinically significant toxicity. Both TIBO and the non nucleotide reverse transcriptase inhibitor nevirapine proceeded rapidly to phase II clinical trials in patients. However it soon became apparent that these non-nucleoside inhibitors rapidly select out HIV mutants in vivo which are resistant to the usual dosages of the respective inhibitors. In the case of nevirapine for example, after only four weeks of therapy virus isolated from patient serum was 100 fold less sensitive to the drug compared with virus isolated from untreated patients (Drug Design and Discovery 1992 8 pp 255-263). A similar pattern has emerged for other non-nucleoside RT inhibitors which have entered clinical trials, Merck""s L-697661 and Upjohn""s delavirdine (U-87201), namely that promising in vitro activity has rapidly produced resistant HIV mutants when administered to patients. Notwithstanding this drawback nevirapine and delavirdine have recently been registered for clinical use, although limited to specific coadministration regimes in an attempt to retard resistance development.
International patent application no WO 95/06034 describes a series of novel urea derivatives which exhibit good in vitro activity against HIV reverse transcriptase and good inhibition of HIV replication in cell culture. However practical deployment of the compounds in WO 95/06034 is hampered by their poor pharmacokinetic performance. Additionally, as with many non-nucleoside reverse transcriptase inhibitors, the compounds presented in WO 95/06034 leave room for improvement in the key parameter of slow resistance development and a favourable pattern of activity against HIV mutants generated by other antiviral regimes.
A poster of xc3x96berg et al at the 1995 ICAR at Santa Fe disclosed inter alia a racemic compound nominally within the abovementioned WO 95/06034 and having the formula: 
At the time the above depicted compound was regarded as of less interest than thiourea variants having a methoxy/acetyl bearing phenyl ring. However, we have now discovered that an alternative substitution pattern manifests an improved resistance pattern in comparison to these prior art compounds in conjunction with good pharmacokinetic performance and a prolonged time to virus resistance. The invention thus provides inhibitors which combine the superior specificity of non-nucleoside inhibitors with the clinical practicality missing from all prior art inhibitors.
In accordance with the invention there are provided compounds of the formula I 
wherein
R1 is halo;
R2 is C,-C, alkyl;
Rx is cyano or bromo;
and pharmaceutically acceptable salts and prodrugs thereof.
The invention further provides pharmaceutical compositions comprising the compounds of formula I and pharmaceutically acceptable carriers or diluents therefor. Additional aspects of the invention provide methods for the inhibition of HIV comprising administering a compound of the formula I to a subject afflicted with HIV. The invention also extends to the use of the compounds of formula I in therapy, such as in the preparation of a medicament for the treatment of HIV infections.
In treating conditions caused by HIV, the compounds of formula I are preferably administered in an amount to achieve a plasma level of around 10 to 1000 nM and more preferably 100 to 500 nM. This corresponds to a dosage rate, depending on the bioavailability of the formulation, of the order 0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day. A typical dosage rate for a normal adult will be around 0.05 to 5 g per day, preferably 0.1 to 2 g such as 500-750 mg, in one to four dosage units per day.
A preferred subset of compounds within claim 2, particularly with regard to pharmacokinetics, has the structure IA: 
where R1 and R2 are as defined above, including the pharmaceutically acceptable salts and prodrugs thereof.
A further favoured subset of compounds within Formula I, particularly with regard to ease of forming prodrugs, comprise compounds wherein Rx is bromo.
Preferably R1 is chloro and more preferably fluoro. Suitable R2 groups include methyl, isopropyl, n-propyl and preferably ethyl.
As depicted above, the cyclopropyl ring is in the cis configuration, allowing two enantiomers, 1S, 2S and 1R, 2R (respectively and non-conventionally denoted 2R,1S and 2S,1R in SE 980016-7 and SE 9800113-4): 
Each of these enantiomers are potent antiretrovirals, although the different enantiomers can display subtle differences in physiological properties. For instance the 1S,2S and 1R,2R enantiomers can show a different pattern of metabolism within the P450 system. The 1S,2S enantiomer of compounds wherein Rx is cyano is particularly preferred as it appears unique in being able to avoid key components of the P450 system. Other retroviral agents such as the HIV protease inhibitor ritonavir interact extensively with the P450 system, leading to an array of undesirable physiological responses including extensive alteration of the metabolism of other co-administered drugs. This is of particular concern with pharmaceuticals administered for a chronic infection where patients can expect to take a number of pharmaceuticals for years, if not decades.
Suitable prodrugs of the compounds of formula I include those of the formula II: 
wherein
R1, R1 and Rx are as defined above,
R3 is H, (CHm)nNR5R6;
R4 is H, C1-C3alkyl, (CHm)nNR5R6, (CHm)nC(xe2x95x90O)R5, (CHm)nOH, OR7, halo, CF3 or CN; or
R3, and R4 together define a 5 or 6 membered fused ring having 0-2 hetero atoms and/or 0-2 unsaturated bonds and/or 0-2 substituents;
R5, is H, C1-C3 alkyl, C(xe2x95x90O)R7 or a peptide of 1 to 4 amino acids;
R6 is H, C1-C3 alkyl; or
R5 and R6 together define a 5 or 6 membered ring having 0 or 1 additional hetero atom and/or 0-2 unsaturated bonds and/or 0-2 substituents;
R7 is H, C1-C12 alkyl, (CHm)nNR5R6;
X and its encompassing circle define a 5 or 6 membered ring having 0 to 3 unsaturated bonds and/or 0 to 3 hetero atoms selected from S, O and N;
m is independently 1 or 2;
n is independently 0, 1 or 2;
and pharmaceutically acceptable salts thereof.
Corresponding prodrugs of compounds wherein Rx is chloro foam a further aspect of the invention.
The ring structure containing X, hereafter referred to the X-ring, may be saturated or have 1-3 unsaturated bonds, including rings with an aromatic character. Preferred X-rings include a cyclohexanyl or cyclohexenyl ring or more preferably a phenyl ring. Other preferred X-rings include morpholino or more preferably a pyridyl ring. Alternatively, X-ring may define a five membered ring such as pentenyl or pyrrolyl.
Suitable fused ring systems for the X-ring in the event that R3 and R4 join to form an optionally hetero-containing ring include napthyl, quinolyl, tetrahydroisoquinolyl, indolyl or benzimidazole ring systems. Suitable substituent rings for the X-ring in the event that R4 and R5 join to form a ring include morpholino and piperidino. These fused or substituent rings may be may be optionally substituted with halo, halomethyl, amino such as (CHm)nNR5R6, C(xe2x95x90O)NR5R6, hydroxy, hydroxymethyl, carboxy, carboxymethyl, C1-3alkyl, C1-3alkoxy and the like.
The X-ring may be spaced from the adjacent carbonyl moiety by a methylene or ethylene group which may be optionally substituted with substituents such as halo, halomethyl, amino, amino methyl, hydroxy, hydroxymethyl, carboxy, carboxymethyl, C1-3alkyl, C1-3alkoxy and the like. It is preferred that the X-ring is adjacent the carbonyl.
Preferably the moiety represented by the X-ring system, R3, R4 and, if present R5-R7 has a somewhat basic character. This can be achieved by selecting a suitably basic heterocycle as the X-ring, such as pyridyl or benzopyridyl. Alternatively or additionally, one or more of R3 to R7 may comprise a basic substituent such as a primary, secondary or tertiary amine, an amino acid etc.
Favoured R3, and/or R1 groups include NH2, N(CH2)2 and NHC1-C3 alkyl, such as NHCH3 or NHCH2CH3. Preferably R3, is in the meta position relative to the carbonyl and its optional spacer, especially where the X-containing ring is phenyl or R3 is in the para position when the X-containing ring is heteroaromatic, such as pyrid-3-yl. The currently preferred value for p and/or n is zero, that is the respective groups are absent.
Preferred compounds of the invention include:
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-acetylpheny)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
and pharmaceutically acceptable salts thereof.
Other preferred compounds include
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
and pharmaceutically acceptable salts thereof
Other convenient compounds of the invention include:
(1R,2R)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)urea,
(1R,2R)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1R,2R)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)urea,
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(IR,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
and their pharmaceutically acceptable salts.
Other convenient compounds include;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
and pharmaceutically acceptable salts thereof.
Preferred compounds of the invention include
(1S,2S)-N-[cis-2-(2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
and their pharmaceutically acceptable salts.
Further preferred compounds include:
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R
N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
and pharmaceutically acceptable salts thereof.
Appropriate pharmaceutically acceptable salts of the compounds of formula I include salts of organic carboxylic acids such as acetic, lactic, gluconic, citric, tartaric, maleic, malic, pantothenic, isethionic, oxalic, lactobionic, and succinic acids, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid and p-toluenesulfonic acid; and inorganic acids such as hydrochloric, hydroiodic, sulfuric, phosphoric and sulfamic acids.
In keeping with the usual practice with HIV inhibitors it is advantageous to co-administer one to three additional antivirals to provide synergistic responses and to ensure complementary resistance patterns. Such additional antivirals may include AZT, ddI, ddC, D4T, 3TC, abacavir, adefovir, adefovir dipivoxil, bis-POC-PMPA, foscarnet, hydroxyurea, Hoechst-Bayer HBY 097, efavirenz, trovirdine, nevirapine, delaviridine, PFA, H2G, ABT 606, DMP-450, loviride, ritonavir, saquinavir, indinavir, amprenavir (Vertex VX 478), nelfianavir and the like, typically at molar ratios reflecting their respective activities and bioavailabilities. Generally such ratio will be of the order of 25:1 to 1:25, relative to the compound of formula I.
While it is possible for the active agent to be administered alone, it is preferable to present it as part of a pharmaceutical formulation. Such a formulation will comprise the above defined active agent together with one or more acceptable carriers and optionally other therapeutic ingredients. The carriers(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any methods well known in the art of pharmacy.
Such methods include the step of bringing into association the above defined active agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.
With regard to compositions for oral administration (e.g. tablets and capsules), the term suitable carrier includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate and other metallic stearates, stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.
Convenient carriers for oral dosing include liquid formulations in the form of solutions, suspensions or emulsions, optionally encapsulated or otherwise presented in unit dose form in a conventional manner. Favoured formulations include acacia/TWEEN/water, TWEEN/water, propylene glycol, vegetable oil (such as peanut, olive and the like) with 10-20% ethanol, vegetable oil/Capmul MGM, Capmul MCM/propylene glycol, methyl cellulose/water, vegetable oil/stearoyl monoester of glycerol, vegetable oil/monounsaturated fatty acid ester of glycerol and the like.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
Formulations suitable for topical administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels, and pastes comprising the active agent and a pharmaceutically active carrier. An exemplary topical delivery system is a transdermal patch containing the active agent. Other topical formulations include antiseptic swabs which release the active agent upon the skin prior to invasive procedures such as injection or capillary blood sampling. Such swabs neutralise HIV in the blood or serum emanating from the invasive procedure thus assisting to prevent transfer of HIV to health care workers via needle stick accidents. Such swabs may comprise sterile surgical gauze pad soaked in a solution of the active agent in a volatile solvent such as ethanol and single packed in a sealed sachet.
Formulations for rectal or vaginal administration may be presented as a suppository or pessary with a suitable base comprising, for example, cocoa butter or a salicylate. Other vaginal preparations can be presented as tampons, creams, gets, pastes, foams or spray formulations containing, in addition to the active agent, such carriers as are known in the art to be appropriate.
Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation from a container of the powder held up close to the nose. Suitable formulations wherein the carrier is a liquid for administration, for example, as a nasal spray or as nasal drops, include aqueous or oily solutions of the active agent.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
A further aspect of the invention provides methods for the preparation of the compounds of Formula I, in particular the cis enantiomers, comprising the Curtius rearrangement of a compound of the formula: 
followed by coupling of a compound of the formula 
and deprotection, wherein R1, R2 and Rx are as defined above and PG is an hydroxy-protecting group.
The methods of the invention can further comprise the step of acylating with an activated compound of the formula III: 
where R3, R4, X and n are as defined above but are optionally protected, and R8 is hydrogen or a conventional activating group. Alternatively the method of the invention may further comprise the step of alkylation with a compound of the formula IIIa 
where n, R3, R4 and X are as defined above, but where exposed amine, hydroxy etc substituents being protected with conventional protecting groups.
Enantiomeric compounds of formula I may thus be prepared by the reaction scheme below: 
The above scheme illustrates the preparation of a (1S,2S) compound of the invention where Rx is cyano, R1 is F and R2 is ethyl, but corresponding methodology is applicable to the other Rx, R1 and R2 variants. The chiral ligand indicated for the fourth step may comprise, for example, a compound of the formula: 
To prepare the 1R, 2R enantiomer, the mirror image chiral ligand is employed. Alternatively, the chiral ligand may be omitted in order to form the racemate.
Prodrugs of the formula II wherein p is 0 can be synthesised by acylating a compound of the formula I with an activated compound of the formula III, 
where R3, R4, X and n are as defined above but are optionally protected, and R8 is hydrogen or a conventional activating group.
Activated compounds of Formula III include the acid halide, acid anhydride, activated acid ester or the acid in the presence of a coupling reagent such as dicyclohexyl-carbodiimide. Representative activated acid derivatives include the acid chloride, formic and acetic acid derived mixed anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinamide derived esters, N-hydroxyphthalimide derived esters, N-hydroxy-5-norbomene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters and the like. Suitable optional protecting groups for compounds of formula III, especially any constituent amines, include those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (John Wiley and Sons, New York, 1981), which is hereby incorporated by reference. N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-vitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Favoured N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz).
The acylation is carried out with conventional esterification conditions such as DMAP and DCC in a solvent such as dimethylformamide or pyridine. Optional protecting getups may be removed with conventional techniques as comprehensively discussed in Greene above, such as TFA, HCl(aq)/dioxane or hydrogenation in the presence of a catalyst to give the compound of Formula II.
Compounds of the Formula II, wherein p is 1 can be prepared by reacting a compound of the formula III with iodochloromethane or mixed dichloro/iodochlor methane under conventional alkylating conditions to form a compound of the Formula IIIa: 
where n, R3, R4, and X are as defined above, but where exposed amine, hydroxy etc substituents being protected with conventional protecting getups. The compound of formula IIIa is then preferably converted to the corresponding iodo derivative by reaction with NaI followed by coupling to the compound of formula I, typically under basic conditions, such as an organic solvent containing sodium hydride.